Doxorubicin (DOX) is an effective anti-tumor agent that is used against a wide range of human malignancies. However, its potential usefulness is limited by an immediate suppression of cardiac function as well as a cumulative dose-related cardiotoxicity that manifests as congestive heart failure. Since DOX-induced cardiotoxicity is at least partially mediated by free radical toxicity;antioxidant therapy would be a useful adjunct to DOX therapy. Fisetin is a free-radical scavenging compound that is present in high concentration in strawberries. Our preliminary studies demonstrated that fisetin is effective in protecting against DOX-induced cardiac dysfunction. We hypothesize that fisetin can confer both short-term and long-term protection against both acute and chronic DOX-induced cardiotoxicity. Fisetin confers short-term protection against oxidative stress by directly blocking free radical-induced damage long-term protection against oxidative stress by inducing Nrf2 and phase 2 enzymes, the endogenous antioxidant defense system in the heart. In Specific Aim 1, we will determine the minimal dose of fisetin needed to protect against acute DOX-induced cardiotoxicity. In Specific Aim 2, we will examine the effect of fisetin on the expression of ERK, Nrf2 and its downstream genes in wild-type and Nrf2 knockout mice. In Specific Aim 3, we will evaluate the clinical potential of fisetin in chronic DOX-induced cardiotoxicity and in cancer cell lines. The information obtained from this study will help identify potential therapeutic agent against DOX-induced cardiotoxicity. PUBLIC HEALTH RELEVANCE: Cancer is one of the leading causes of mortality in America today. Many cancer patients undergo chemotherapy with doxorubicin (DOX), which causes heart damage as an unfortunate side effect. Our proposed work will determine whether fisetin can reduce the incidence of DOX-induced cardiac injury and enhance the anti-tumor activities of DOX. A diet consisting of 16 mg fisetin or 100 g of strawberries every day taken before and after chemotherapy may represent an inexpensive, effective, and safe way to limit DOX-induced cardiac damage.